The single-player campaign will feature two connected storylines, one set in the 1970s through 1980s and the other in 2025. The protagonist of Black Ops, Alex Mason returns as the protagonist in the Cold War section, where he will be f!ghting in proxy wars for the United States in the Cold War. Known locations for this section of the game include multiple sites in Central America and in Afghanistan during the Soviet invasion. This section of the game will also see the rise to infamy of the game's primary antagonist, Raul Menendez. Mason's friend and colleague Frank Woods will also return, and narrate the story into the 2025 section of the game. The 2025 section of the game features Alex Mason's son David as a protagonist. In it, a new cold war has broken out between China and the United States after China bans the export of rare earth elements following a cyber-attack that cripples the Chinese Stock Exchange. In this era, war is defined by robotics, cyber warfare, unmanned vehicles and other modern technology. Taking advantage of this stand-off, Menendez attempts to bring the two powers to a full-blown war by inciting conflicts between the two. Known locations for this section of the game include Los Angeles, Singapore and Socotra, Yemen.

In the 2025 section of the game, the player will have access to special 'Strike Force missions', that feature permanent death and the outcome of which can affect the course of the campaign's storyline. It has been hinted at that the side-plot of Viktor Reznov and his relationship with Alex Mason, which began in Black Ops, will be continued in Black Ops II.

Both Multiplayer and Zombies Modes have been altered to give veteran players a new experience with much more choices.